Protein essential to the spread of malaria uncovered

Master switch discovered that triggers the development of sexual forms of the malaria parasite

Continuous transmission by transfer of blood caused a malaria parasite of mice to lose its ability to make sexual forms, which are only required for transmission by mosquitoes. The genetic defects shared by three lines selected in this way led to the discovery of the ap2-g gene
[doi: 10.1038/nature12970]

For the first time, researchers have identified a single protein that acts as the master switch to trigger the
development of sexual forms of the malaria parasite, a stage essential for the spread of the disease.

The protein, AP2-G, is necessary for switching on genes that control the development of precursor malaria cells to the
male and female forms of the parasite - the only stage that is infectious to mosquitos. This solves a long-standing
mystery in malaria biology and has important implications for malaria-control strategies.

Sexual reproduction is a vulnerable stage of the parasite's complicated life cycle. This stage can only occur in the
gut of the mosquito after it has sucked the precursor parasite cells out of a person's blood.

"Current drugs treat patients by killing the sexless form of the parasite in their blood - this is
the detrimental stage of the malaria lifecycle that causes illness," says Dr Oliver Billker, co-lead author from
the Wellcome Trust Sanger Institute. "However, it is now widely accepted that to eliminate malaria
from an entire region, it will be equally important to kill the sexual forms that transmit the disease."

The ability of the malaria parasite to produce precursor cells to the sexual male and female form of the parasite can
be lost through continuous culturing in the lab or continuous blood transfer. The team generated three parasite cell
lines that have lost this ability in the lab.

They sequenced the genomes of these parasites and found that common mutations to the ap2-g gene in all three
cell lines appeared to underlie the inability of the parasite to progress to the sexual-stage of its lifecycle.

" It is now widely accepted that to eliminate malaria from an entire region, it will be equally important to kill
the sexual forms that transmit the disease. "

Dr Oliver Billker

To confirm these observations, the team silenced the ap2-g gene in the parasite and found that the manipulated
parasites lost the ability to generate sexual stage parasites.

"Our studies discovered that if we switch off AP2-G in a parasite cell, then that cell cannot grow
into a sexual-stage parasite," says Dr Andy Waters, co-lead author from the University of Glasgow. "This means that the parasite cannot move from the infected person back into the mosquito to continue the
cycle, making transmission of that parasite from one human to another impossible."

Furthermore, when this mutated gene was then repaired through 'gene therapy', the parasites regained the ability to
progress to the sexual stage. Combined with other experiments, their results showed that sexual-stage malaria parasites
are produced only when the AP2-G protein is in good working order.

"Having discovered the master switch, we can now begin to unravel how exactly sexual parasite
stages form and get ready to transmit malaria," says Dr Katarzyna Modrzynska, author from the Wellcome Trust
Sanger Institute. "This will reveal new ways in which drugs and vaccines can be developed to stop
transmission."

This research paper will be published in Nature along with a second paper that separately details the role of
AP2-G as a master switch in controlling sexual stage commitment of malaria parasites.

"Exciting opportunities now lie ahead for finding an effective way to break the chain of malaria
transmission by preventing the malaria parasite from completing its full life cycle," says Dr Manuel
Llinás, from Penn State University, who is lead author of a second study also describing the discovery of AP2-G.
"This sexual-stage bottleneck is an enticing target for interventions to prevent this comparatively
small, yet critical number of sexual parasites from forming."

These studies open the way to the development of screens for effective drugs that could disable commitment to sexual
development and prevent transmission.

Notes to Editors

Publication details

A cascade of DNA-binding proteins for sexual commitment and development in Plasmodium.

Department of Biochemistry and Molecular Biology and Center for Infectious Disease Dynamics, The Pennsylvania State
University, State College, PA, USA

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